1. Technical Field of the Invention
The present invention relates to an improved process for the preparation of Amorolfine base, which is an intermediate used in the production of Amorolfine (AMF) hydrochloride (Amorolfine HCl).
2. Description of Background and/or Related and/or Prior Art
Amorolfine HCl is an active pharmaceutical ingredient (API) formulated into topical anti-mycotic (antifungal) compositions.
FR 2,463,767 describes methods of producing Amorolfine HCl and intermediates in such production. In particular, a method for the production of Amorolfine base (AMF base), which is a compound of formula (I):
is described, the method involving the step of reacting a compound of the formula (a):
with a compound of the formula (b):
in a Friedel-Crafts alkylation to form AMF base. The suggested catalysts are those known for use as Friedel-Crafts catalysts, such as aluminum chloride, iron chloride, zinc chloride, boron trifluoride, hydrogen fluoride, sulfuric acid, and phosphoric acid. Sulfuric acid is stated to be the preferred catalyst. To provide a compound of the formula (b):

FR 2,463,767 suggests using tertiary alcohols such as 2-methyl-2-butanol, or tertiary chlorides such as 2-chloro-2-methylbutane. However, only 2-methyl-2-butanol is exemplified. The reaction temperature is noted as not being of critical importance but is suggested to be, in general, from 0° to 50° C., preferably from 18° to 20° C.
On another side, it is generally known that Friedel-Crafts catalysts show different activities in the alkylation reaction of aromatic compounds. As disclosed in the “KIRK-OTHMER Encyclopedia of Chemical Technology”, 4th Edition, Vol. 11, 1994, page 1071 (Table 1), more active is the Friedel-Crafts catalyst, more expected are side reactions.
There remains a need for improved processes for the production of Amorolfine salts, for example Amorolfine HCl, and its intermediates, such as Amorolfine base.